Gold nanoparticle (GNP)-mediated photothermal cancer therapy (PTT) treats primary tumors using a laser source to heat GNPs tuned to strongly absorb light in the NIR spectral region. While the technology is highly promising, clinical application of the technique is limited by the need for a priori knowledge of tumor location to determine the site of laser application. While the immune response to GNP-enabled PTT has not been carefully examined, it is known that thermal ablation induces production of pro-inflammatory cytokines and chemokines that can activate innate immune cells including myeloid-derived suppressor cells (MDSCs), which suppress antitumor T cells and facilitate tumor survival and proliferation. Furthermore, activation of immune cells may promote growth of metastatic lesions after GNP-enabled PTT. These challenges exist for all ablative thermal therapies. A GNP-enabled PTT strategy that favored generation of tumor-specific T cells while minimizing the immune suppressive effects of MDSCs could significantly enhance efficacy both for primary and distant metastatic lesions. Unlike other ablative therapies, therapy employing GNPs offers the potential for co- delivery of therapeutic agents that target MDSCs and other cellular constituents of the reticuloendothelial system, including antigen presenting dendritic cells (DCs). Recent studies have found that immunostimulatory CpG oligonucleotides (ODN) can promote tumor regression by reducing the immune suppressive activity of MDSCs and activating lymph node resident DCs to increase stimulation of tumor-specific T cells. Based on these studies, we hypothesize that GNPs conjugated to CpG ODN will enable NIR-activated PTT on accessible tumors while decreasing the effects of immune suppressive MDSCs and boosting DC function. In this project, we first investigate the role of MDSCs in promoting metastatic tumor growth and suppressing tumor-specific T cells following GNP-enabled PTT. We will then evaluate if GNPs coated with CpG ODN can reverse the effects of MDSCs in vivo following PTT. Finally, we will evaluate whether CpG ODN coated GNPs can be used in combination with PTT to destroy accessible tumors while stimulating lymph node resident DCs, providing an in situ cancer vaccine. Using nanocarriers to deliver CpG offers a number of potential advantages including reduced degradation during delivery and ability to adjust biodistribution through physicochemical feature selection. Moreover, preliminary data indicates increased effects of CpG ODN in vitro using GNP delivered CpG ODN as opposed to the equivalent dose of ODN alone. The potential impact of GNP-CpG on MDSCs is particularly important in light of preliminary data suggesting GNP-enabled PTT alone can promote growth of metastatic lesions in some cases. To further develop the clinical potential of PTT, this project will investigate why and when growth of metastatic lesions may occur after PTT, whether this effect can be reversed, and how GNP-enabled PTT based therapeutic approaches might be developed that enable effective treatment not only of primary tumors but secondary tumors and metastatic lesions as well.